MOLECULAR MECHANISMS OF GLUCOCORTICOID HORMONE ACTION

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Glucocorticoids and progestins regulate numerous processes in normal physiology and disease including pregnancy, lung and breast development, stress response, inflammation, and cancer. The receptors for these steroid hormones control these processes by regulating transcription of target genes. Our long term goal is to understand these regulatory mechanisms. Such knowledge could drive the improvement of existing therapeutic regimens and the development of novel avenues for intervention, particularly in endocrine-dependent neoplasia and inflammatory disease. The focus of the first aim is the coupling of steroid response mechanisms with other signal transduction pathways. The activation of inhibition of specific cellular signal transduction pathways can dramatically influence steroid receptor-mediated transcriptional regulation. The hormone response may be potentiated or inhibited up to 10-fold. We propose to identify the region of the TATA biding protein that is the target for the coupling between the protein kinase A pathway and glucocorticoid-dependent transcription and to identify the mediators of this coupling. In some circumstances, steroid receptors may even be activated in the absence of hormone. Additional experiments will investigate the basis of the differential capacity of glucocorticoid and progesterone receptors to undergo hormone-independent activation. We will test the hypothesis that this is a functional consequence of differential localization of the glucocorticoid and progesterone receptors. In the second aim we will focus on the mechanisms that govern differential control of gene expression by glucocorticoid and progesterone receptors. Since several steroid receptors have similar, if not identical, DNA sequence recognition properties, the question of how differential regulation of target genes is accomplished is central to understanding the biology of hormone action. A comprehensive approach is proposed to identify new examples of differential induction and to investigate the mechanisms that govern differential responsiveness of target promoters. Central to these studies is the use of a retrovirus-based trap system to identify differentially regulated promoters and chromosomal locations.